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A Randomized, Controlled Trial of Oxycodone Versus Placebo in Patients With PostHerpetic Neuralgia and Painful Diabetic Neuropathy Treated With Pregabalin
The Journal of Pain, Vol 11, No 5 (May), 2010: pp 462-471 Available online at www.sciencedirect.com
A Randomized, Controlled Trial of Oxycodone Versus Placebo in Patients With PostHerpetic Neuralgia and Painful Diabetic Neuropathy Treated With Pregabalin Che S. Zin,* Lisa M. Nissen,* James P. O’Callaghan,y Stephen B. Duffull,*,x Maree T. Smith,*,z and Brendan J. Moore*,y * The University of Queensland, School of Pharmacy, St Lucia Campus, QLD 4072, Australia. y Greenslopes Private Hospital, QLD 4120, Australia. z Centre for Integrated Preclinical Drug Development, St Lucia Campus, QLD 4072, Australia. x University of Otago, School of Pharmacy, Dunedin, 9054, New Zealand.
Abstract: The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/ day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the painintensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain. Perspective: Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in 40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin. ª 2010 by the American Pain Society Key words: Pregabalin, oxycodone, postherpetic neuralgia, painful diabetic neuropathy.
N
europathic pain is the result of a primary lesion or dysfunction in any part of the nervous system.21 Neuropathic pain is often classified into 2 groups, central and peripheral.6 Peripheral neuropathic pain presents commonly in clinical practice and 2 of its most prevalent types are postherpetic neuralgia (PHN) and Received December 17, 2008; Revised August 7, 2009; Accepted September 1, 2009. Supported by a research grant from The Gallipoli Research Trust Foundation, Greenslopes Private Hospital. C.S.Z. was supported by a PhD scholarship funded by the Malaysian Government. Address reprint requests to Dr Lisa Nissen, The University of Queensland, Room 3308C, Steele Building, School of Pharmacy, St Lucia Campus, Brisbane, Australia, 4072. E-mail: [email protected] 1526-5900/$36.00 ª 2010 by the American Pain Society doi:10.1016/j.jpain.2009.09.003
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painful diabetic neuropathy (PDN).13,14,31 PHN is a serious complication of shingles or herpes zoster infection while PDN is a common long-term complication of diabetes mellitus. Although currently available treatments have been shown to be effective for the treatment of neuropathic pain, dose-limiting side effects and drug interactions limit their usefulness in some patients. It is estimated that 40 to 60% of patients experience some degree of pain relief with currently available treatments, leaving the remainder with unremitting pain.38 Over the last 15 years, the multiplicity of underlying mechanisms contributing to the development and maintenance of neuropathic pain have become clearer.22,37 With multiple contributing mechanisms, the administration of drug treatments in combination, each producing
Zin et al pain relief through distinctly different mechanisms, may have the potential to produce superior patient outcomes relative to large doses of individual drugs administered alone.1 This suggested approach has the potential to improve efficacy outcomes and reduce adverse effects in patients who achieve only partial pain relief from a single agent or who experience dose-limiting side effects from large doses of a single antineuropathic agent.3 Based on the efficacy of currently available treatments for neuropathic pain, combinations of 2 or more drugs from the following treatments groups—gabapentin/pregabalin, duloxetine/venlafaxine, lidocaine patch 5%, opioid analgesics (oxycodone and morphine), and tricyclic antidepressants (TCAs)—are worthy of future clinical-trial evaluation.4 Preclinical studies indicate that spontaneous ongoing pain symptoms secondary to central sensitization of the dorsal horn of the spinal cord may be alleviated by drugs acting to block calcium (Ca21) channels or sodium (Na1) channels, or by boosting descending inhibitory mechanisms.1 Thus, drugs such as gabapentin and pregabalin that are thought to produce pain relief through inhibition of presynaptic calcium channels2,7 may produce additive or possibly synergistic benefit when combined with an opioid, or with an antidepressant.3,24 The combination of morphine and gabapentin has been shown to be superior to morphine alone, gabapentin alone or placebo, in relieving pain and improving daily functions in patients with PHN or PDN.9 These benefits were observed at lower doses with the combination of drug treatment than for a single therapy. Another combination study in patients with PDN demonstrated that the combination of gabapentin and oxycodone produced greater treatment effects than gabapentin/ placebo.12 Thus far, clinical trials evaluating the analgesic efficacy of a combination of pregabalin and opioid have not been published. Pregabalin has linear pharmacokinetics and a faster onset of action compared with gabapentin which make pregabalin a superior option for use in analgesic combination studies.12 Furthermore, as pregabalin requires twice-daily dosing, rather than the thrice-daily dosing for gabapentin, pregabalin’s longer interdosing interval has the potential to improve patient compliance.4 Although oxycodone has been shown to have efficacy for the treatment of PHN or PDN in a number of studies, dosages in the range of 20 to 120 mg/day are associated with a high frequency of unwanted opioid-related side effects.10,35,36 Hence, this study was designed to assess whether or not administration of a low dose of oxycodone (10 mg/day) administered in combination with pregabalin would enhance the pain-relieving efficacy of pregabalin for the symptomatic relief of patients with either PHN or PDN. For the treatment of nociceptive pain, this low dose of oxycodone at 10 mg/day has been shown to be beneficial when combined with other analgesics such as paracetamol and NSAIDs.25,33 Similar combination studies are lacking in neuropathic pain.
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Methods Study Design This study was a randomized, double-blind, placebocontrolled, parallel-group, single-center clinical trial to evaluate the efficacy and safety of a low fixed dose of oxycodone (10 mg/day) or placebo in combination with pregabalin, administered according to an openlabel forced-titration dosing regimen in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). This study was conducted at Greenslopes Private Hospital (GPH), Brisbane, Australia. Patients were recruited through a number of methods including advertisements in local, state, and national newspapers, diabetes Australia (Queensland) magazines, faxouts/newsletters to local general practitioners, and referral to the GPH Pain Clinic. Recruitment was undertaken from July 2006 until December 2007. The study was approved by the Human Research Ethics Committee of GPH and from the Medical Research Ethics Committee of The University of Queensland. Inclusion criteria included: 1) male or female outpatients aged $18 years; 2) established diagnosis of PHN of at least 3 months’ duration but no more than 5 years’ duration after crusting of the last lesion; 3) established diagnosis of PDN for 1 to 5 years; 4) a pain-intensity score of at least 4 cm on a 10-cm visual analogue scale (VAS) for the past 24 hours; 5) no coexisting moderate to severe pain that could potentially confound the assessment or self-evaluation of neuropathic pain due to PHN or PDN; 6) no evidence of moderate or severe renal impairment, ie, creatinine clearance must be >30 mL/min (calculated using Cockcroft-Gault equation); and 7) female patients had to be nonpregnant, nonlactating and either postmenopausal, surgically sterilized, or using an appropriate method of contraception. Exclusion criteria included: 1) known allergic reaction or contraindicated to pregabalin or oxycodone; 2) had other unstable medical conditions such as myocardial infarction, cardiac conduction defect, severe pulmonary disease, and severe depression; 3) taking monoamine oxidase inhibitors; and 4) history of substance abuse involving agents such as opioids and alcohol.
Baseline This study involved 4 clinic visits over a period of 6 weeks. During visit 1, patients were assessed for compliance with the study inclusion criteria, a full medical history was obtained, and physical examination performed. Patients who met all of the inclusion criteria and none of the exclusion criteria, and who gave written informed consent, were recruited to enter a 7-day studywashout period. Medications that might possibly affect painful symptoms including opioid analgesics, anticonvulsants (eg, gabapentin, pregabalin, sodium valproate, lamotrigine), tricyclic antidepressants, capsaicin, benzodiazepines, and skeletal muscle relaxants were gradually withdrawn during the study-washout period. Patients were permitted to continue taking paracetamol as rescue medication,
464 aspirin (up to 325 mg/day) for cardiovascular prophylaxis, and serotonin selective reuptake inhibitors for treatment of depression. During baseline and treatment phases, each day upon awakening patients recorded pain-intensity scores evaluated for the previous 24 hours on a 10-cm VAS (0 = no pain, 10 = worst possible pain) in their study diary. The question about the pain intensity was ‘‘how do you feel today?’’ It was explained to patients that they were required to rate their pain intensity in the past 24 hours and this was reinforced to patients during telephone calls from study investigators.
Treatments To be eligible for entry into the main study, patients had to have recorded pain-intensity scores in their study diary for at least 4 out of the previous 7 days of the studywashout period when they returned to the study center for visit 2. Additionally, patients had to continue to meet all of the inclusion criteria and none of the exclusion criteria. During visit 2, patients were randomized to receive oxycodone mixture 2.5 mL (2 mg/mL) or placebo mixture 2.5 mL twice a day for 1 week. Patients were assigned to 1 of 2 treatment groups using a computer-generated randomization number in block sizes of 10. The randomization sequence list was controlled independently by the clinical pharmacist at GPH. All of the characteristics (appearance, taste, and method of administration) of the oxycodone and placebo mixture were identical to ensure that study blinding was maintained. The oxycodone and placebo mixtures were prepared by the Central Pharmacy of the Royal Brisbane and Women’s Hospital, and the pregabalin (Lyrica) marketed by Pfizer, was purchased from commercial sources. All the study medications were supplied to patients by the clinical-trial pharmacist at the GPH. After a 7-day treatment period with either oxycodone alone or placebo alone, patients returned to the GPH pain clinic for visit 3, and they were then started on pregabalin while continuing with the same dosage of either oxycodone mixture or placebo mixture for 4 weeks. The starting dose for pregabalin was 75 mg once daily, which was titrated at weekly intervals to 75 mg twice daily (bd), 150 mg bd, then to a maximum dose of 300 mg bd. Dosage escalation was terminated once the patient achieved the maximum dosage of 600 mg/day or the maximum tolerated dose (the immediate dose level less than the dose which caused intolerable side effects). Patients then remained on this dose (pregabalin plus oxycodone or placebo mixture) for a further 7-day period to complete the study. Accordingly, patients who tolerated the maximum dose of pregabalin or the maximum tolerated dose at lower doses of pregabalin, completed the study in less than 6 weeks. After taking the final study medication for 7 days, patients returned to the study centre for a final review (visit 4). Final assessment, including a full medical and physical examination, were performed. The dose level that produced a clinical benefit (considered to be at least a 2 cm drop in VAS pain scores and
Pregabalin and Oxycodone, Clinical Trial in PHN and PDN a VAS pain score <4 cm) was recorded for the primary efficacy measure. Side effects (dizziness, drowsiness, nausea, vomiting, and constipation) that occurred at this dose level were also recorded. In addition, the VAS score and side effects were recorded at each dose level up to the maximum dose or maximum tolerated dose. Patients were allowed to use paracetamol as their breakthrough medication during the study period. During the trial, the study investigator made regular telephone calls to patients to monitor their well-being, to ensure that the patients were taking their study medication, and that they were completing the study diary appropriately. The titration of pregabalin medication was performed via telephone consultation between a study investigator and the patient.
Efficacy Measures Primary Efficacy Outcome Measure The primary efficacy measure was at least a 2-cm drop in the pain-intensity score23 and a pain-intensity score of less than 4 cm measured by VAS from baseline, following pregabalin dosage escalation. This was evaluated from each patient’s study diary and was considered as the criteria for a treatment success for this study. The baseline pain score for this study is defined as the mean of the last 4 pain-diary entries prior to initiation of oral treatment with either the oxycodone or the placebo mixture. The VAS pain scores during the pregabalin dosage escalation were obtained by averaging the 4 daily pain-intensity scores recorded prior to forced titration of the pregabalin dose to the next level. Supplementary measures for primary efficacy included weekly pain score and responder rates (based on $50% pain reduction from baseline) evaluated from each patient’s study diary. The calculation for responder rates was similar to the calculation for the primary efficacy measure. The mean pain scores had to decrease $50% from the baseline following the pregabalin dose escalation for the patient to be considered as a responder.
Secondary Efficacy Outcome Measures Secondary outcome measures were evaluated from questionnaires completed during the study.
Sleep Interference Score Sleep interference was assessed using a 10-cm VAS with the delimiters ‘‘did not interfere’’ and ‘‘cannot sleep at all due to pain’’.19 Sleep interference was evaluated from each patient’s study diary entries by comparing the degree of sleep interference from baseline to the study endpoint.
Neuropathic Pain Scale (NPS) The NPS8 is specifically designed for measuring pain qualities associated with neuropathic pain conditions. This instrument has 10 questions that consist of 8 descriptors for pain conditions, 1 descriptor for pain intensity, and 1 descriptor for unpleasantness.15 The descriptors of the pain conditions include: ‘‘sharp’’, ‘‘hot’’, ‘‘dull’’,
Zin et al ‘‘cold’’, ‘‘sensitive’’, ‘‘itchy’’, ‘‘deep’’, and ‘‘surface’’. NPS was administered at every study visit.
465 15
The
Short-Form 36 (SF 36) The SF-3634 is a self-administered questionnaire consisting of 8 health concepts: 1) limitation in physical activities because of health problems (physical functioning); 2) limitations in social activities because of physical or emotional problems (social functioning); 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health; 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. This SF-36 was administered at visit 1, visit 2 and visit 4.
Profile of Mood States (POMS) The POMS20 is a self-administered instrument and is widely used to assess changes in mood in many neuropathic pain trials.17,27,28 The POMS consists of 65 questions measuring 6 different subscales: 1) tensionanxiety; 2) depression-dejection; 3) anger-hostility; 4) fatigue-inertia; 5) confusion-bewilderment; 6) vigoractivity. The POMS was administered at visits 1, 2, and 4.
Trail Making Test B (TMTB) The TMTB32 was used for the assessment of cognitive performance. The TMTB requires the patient to connect letters and numbers in alternating order (1-A-2-B-3-C, etc) in as little time as possible.16 This test was administered at visits 1, 2, and 4.
Patient Global Impression of Change (PGIC) The PGIC5 was utilized to assess global improvement based on patient rating. The PGIC consists of 7 descriptors (‘‘very much improved’’, ‘‘much improved’’, ‘‘minimally improved’’, ‘‘no change’’, ‘‘minimally worse’’, ‘‘much worse,’’ and ‘‘very much worse’’).5,30 The PGIC was administered at the end of the study.
Clinician Global Impression of Change (CGIC) The CGIC5 was utilized to assess global improvement based on clinician rating. The CGIC consists of 7 descriptors (‘‘very much improved’’, ‘‘much improved’’, ‘‘minimally improved’’, ‘‘no change’’, ‘‘minimally worse’’, ‘‘much worse,’’ and ‘‘very much worse’’).5,30 The CGIC was administered at the end of the study. Safety measures were based on the frequency and severity of adverse events which were assessed based upon the entries in the study diary and during openended questioning by the investigator at each study visit.
Power Analysis The power of this study was assessed using clinical-trial simulation techniques. Using this technique, a virtual clinical trial was created and outcomes simulated for 200 replications of the virtual trial. The power was calculated as the proportion of times that replications of the trial showed a difference between the 2 treatment arms. The virtual trial was designed to have similar fea-
tures to the actual clinical trial conducted here, ie, was a parallel-design dose-escalation study. All simulations were performed using MATLAB (The MathCorks Inc, Natick, MA). These simulations indicated that enrolling a total of 50 patients over the 2 treatment groups, ie, 25 patients per arm but allowing replacement for dropouts, would provide a power of approximately 80% to detect a clinically significant difference between the 2 treatment arms with an alpha error (2a) of 5%. A clinically significant difference was defined as both a drop of 2 cm on the VAS as well as a final VAS score of less than 4 cm. The baseline VAS score was 7 cm (62 cm) [mean 6 SD], with a minimum VAS score of 4 cm. The expected mean change in VAS score from pregabalin alone was a reduction in 2 cm and for the combination of pregabalin and oxycodone a reduction of 3.5 cm. The virtual clinical trial included dropouts due to lack of tolerability in a dosedependent manner with dropouts reaching 20% with daily doses of pregabalin approaching 300 mg. These dropouts are based on the reports of gabapentin studies26,29 in the treatment of postherpetic neuralgia and an assumption that the equipotent dose ratio of pregabalin and gabapentin was approximately 6. Based on this and the possibility of random dropouts, then recruitment of 63 patients would be sufficient to ensure that 50 patients completed the study.
Statistical Methodology All analyses were conducted on an intention-to-treat basis. All randomized patients were included in the safety analyses and all randomized patients with baseline and at least 1 postbaseline efficacy assessment were included in the efficacy evaluations. Missing observations due to discontinuation of treatment were extrapolated by carrying forward the mean of the last 4 observations (LOCF) immediately before discontinuation through to the final visit. All testing was 2-sided and was performed using Number Cruncher Statistical Software (NCSS, Kaysville, UT, 2004). The percentage of patients who obtained at least a 2-cm drop in the VAS score relative to baseline and <4 cm on the VAS pain score (primary efficacy measure), and who achieved $50% pain reduction, gave the responder rates of the 2 treatment groups, and these were compared by the Chi Squared test. Comparison between treatments in the change from baseline in mean pain scores, mean sleep scores, NPS, SF-36 domains, POMS total scores and TMTB were analyzed using an analysis of covariance (ANCOVA) model. The fixed terms of this model were treatment, type of pain, and baseline mean score as a covariate. The data for POMS were not normally distributed, and so they were normalized using rank transformation. PGIC and CGIC were analyzed using the Cochrane Mantel Haenszel (CMH) test. Safety analyses were conducted for all randomized patients who received at least 1 dose of study medication (safety population). The number of each type of adverse event was analyzed using descriptive statistical methods.
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Pregabalin and Oxycodone, Clinical Trial in PHN and PDN Screened N=134 Did not meet criteria N=38 Did not tolerate washout period N=5 Other/administrative N=29 Randomized N=62
Oxycodone N=29
Placebo N=33
Total withdrawn N=5 (Adverse events N=3 Other/administrative N=2)
Total withdrawn N=4 (Lack of efficacy N=1 Other/administrative N=3)
Pregabalin/oxycodone N=24
Pregabalin/placebo N=29
Total withdrawn N=1 (Adverse events N=1)
Total withdrawn N=1 (Lack of compliance N=1)
Completed N=23
Completed N=28
Figure 1. A consort diagram.
Results Patient Disposition A total of 134 patients were screened with 62 patients randomized to receive treatment (Fig 1). Of these 62 patients, 29 received pregabalin/oxycodone and 33 received pregabalin/placebo. In the pregabalin/oxycodone group, 2 patients withdrew before taking any study medication due to administrative issues and were not included in the analysis. In the pregabalin/placebo group, 3 withdrawals were not included in the analysis as these patients withdrew before they started taking study medication due to administrative issues. Overall, 82% (51/62) of total randomized patients completed the entire study, with 79% (23/29) of patients in the pregabalin/oxycodone group and 85% (28/33) of patients in the pregabalin/placebo group.
Patient Demographics Patient baseline characteristics are summarized in Table 1. There were more males than females in the pregabalin/oxycodone group compared with the pregabalin/placebo group. Additionally, patients in the pregabalin/oxycodone group reported a slightly shorter duration of PHN, but longer duration of PDN, compared with patients in the pregabalin/placebo group. Importantly, the mean (6SEM) baseline pain scores were similar (P > .05) in the pregabalin/oxycodone group (6.85 6 .30) compared with the pregabalin/placebo group (6.73 6 .29).
Primary Efficacy Measure There was no significant difference in the overall proportion of patients who achieved at least a 2-cm drop in
Patients Demographic and Baseline Characteristics
Table 1.
CHARACTERISTICS
PGB/OXY (N = 29)
Sex Male n (%) 19 (65.5) Female n (%) 10 (33.4) Age Mean 6 SD 70.27 6 11.49 Range 50–91 Race White n (%) 27 (93.1%) Other n (%) 2 (6.8%) Weight, kg 83.9 6 21.55 mean 6 SD Height, cm 171.28 6 9.06 mean 6 SD Disease history PHN n (%) 15 (51.7) Duration of PHN-year, 1.62 6 1.22 mean 6 SD PDN n (%) 14 (48.2) Duration of PDN-year, 4.5 6 3.71 mean 6 SD Baseline pain score, 6.85 6 .30 mean 6 SEM
PGB/PLA (N = 33)
TOTAL PATIENTS (N = 62)
16 (48.5) 17 (51.5)
35 (56.4) 27 (43.5)
66.8 6 11.7 45–87 33 (100) 0 (0) 82.2 6 19.33
60 (96.7) 2 (3.2)
167 6 10.82
17 (51.5) 2.76 6 1.8
32 (51.6)
16 (48.4) 2.88 6 1.75
30 (48.3)
6.73 6 .29
Abbreviations: Pgb/Oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo; n, number of patients; PHN, post-herpetic neuralgia; PDN, painful diabetic neuropathy.
the pain-intensity score and a pain-intensity score of less than 4 cm on the VAS in the pregabalin/oxycodone (69%) and pregabalin/placebo (76%) groups (P = .581, chi squared test). Analysis at different dose levels showed that a greater proportion of patients in the pregabalin/ oxycodone group achieved a treatment success at lower doses of pregabalin (75 and 150 mg/day [58% and 65%]) compared with patients in the pregabalin/placebo group (52% and 62%), but this did not reach statistical significance (P > .05, chi squared test) (Fig 2). A majority of patients in the pregabalin/placebo group achieved treatment success at higher doses of pregabalin (300 and 600 mg/day). As doses were titrated to the maximum tolerated dose, it was shown that at pregabalin 600 mg/day, there were no additional new patients who obtained treatment success either for the pregabalin/ oxycodone group or for the pregabalin/placebo group (Fig2).
Supplemental Measures of Primary Efficacy Weekly mean pain scores were improved in both groups at the study endpoint. The results showed an overall decrease of 3.59 (52.4%) for the pregabalin/oxycodone group and 4.02 (59.7%) for the pregabalin/placebo group. There was no significant difference in pain reduction between the 2 groups (P = .074, ANCOVA) (Table 2). Responder rates based on $50% pain reduction from baseline to endpoint were not significantly different
Zin et al
467
80
Pgb/oxy
75.9
Pgb/pla
69.2
75.9 69.2
65.4 62.0 57.7
60
% of Patients
51.7
40
34.5 30.8
Safety Measures
20
0
Seventeen and thirty percent of patients in the pregabalin/oxycodone group rated themselves as very much and much improved on the PGIC scale compared with 21% and 54% of patients in the pregabalin/placebo group. The differences between the groups were not statistically significant (P = .868, CMH). The CGIC findings also showed a similar trend to the PGIC scale and there was no significant difference between the 2 groups (P = .866, CMH).
Oxy/pla
Pgb 150 mg/d Pgb 75 mg/d
Pgb 600 mg/d
Pgb 300 mg/d
Figure 2. Treatment success at different dosage levels. Pgb/oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo; week 1, baseline; week 2, oxycodone/placebo; week 3, pregabalin 75 mg/day and oxycodone/placebo; week 4, pregabalin 150 mg/ day and oxycodone/placebo; week 5, pregabalin 300 mg/day and oxycodone/placebo; week 6, pregabalin 600 mg/day and oxycodone/placebo. between the 2 treatment groups (P = .551, chi squared test). Fifty-eight percent (15/26) of patients treated with pregabalin/oxycodone experienced $50% pain reduction, compared with 66% (19/29) of patients treated with pregabalin/placebo (Fig 3).
Secondary Efficacy Measures Both treatment groups were improved in all secondary efficacy measures at the end of the study. There were no significant differences in all secondary efficacy measures except in certain domains of the NPS and the SF-36 (Table 2). For the NPS, the pregabalin/oxycodone group had significant improvement in cold pain (P = .035, ANCOVA), while the pregabalin/placebo group demonstrated significant improvement in sharp (P = .042, ANCOVA) and hot pain (P = .005, ANCOVA). For the SF-36, patients in the pregabalin/oxycodone were significantly improved in the general health domain (P = .048, ANCOVA) while patients in the pregabalin/placebo obtained significant improvement in the mental-health domains (P = .004, ANCOVA) (Table 2). The highest dose/maximum tolerated dose of pregabalin at 600 mg/day was achieved in 52% (n = 14/27) of patients treated with pregabalin/oxycodone compared with 57% (n = 17/30) of patients treated with pregabalin/placebo. The average pregabalin dose for patients in the pregabalin/oxycodone group was 227.6 mg/day and 230.6 mg/day for patients in the pregabalin/placebo group. There was no significant difference (P > .05) between the pregabalin/oxycodone group and the pregabalin/ placebo group in the overall mean daily dose for concomitant rescue medication of paracetamol evaluated from the patient study diaries.
The occurrence of adverse events was comparable between the pregabalin/oxycodone group (89%) and the pregabalin/placebo group (80%) (P = .476, Fisher’s exact test), with the overall rating for most of the adverse events being mild in intensity (77–88%) regardless of the treatment group (Table 3). The most commonly reported adverse effects were dizziness, drowsiness, constipation, nausea, headache, and tiredness regardless of the treatment group (Table 3). Of these commonly seen adverse events, constipation and itch were significantly higher in the pregabalin/oxydocone group compared with the pregabalin/placebo group (P < .05, Fisher’s exact test). One patient in the pregabalin/oxycodone group had angioedema during the study but it was not considered to be associated with the study medication but rather due to a change in the patient’s antihypertensive medication. Weight gain of $4% was reported in 8.6% of patients in the pregabalin/oxycodone group and 10.7% of patients in the pregabalin/placebo group. None of the patients experienced weight gain >7% regardless of treatment group. Four patients (15%) in the pregabalin/oxycodone group discontinued the study due to adverse events and none (0%) of the patients in the pregabalin/placebo group discontinued due to adverse events. Of the 4 patients who discontinued in the pregabalin/oxydocone group, 3 withdrew during the first week of treatment with oxycodone alone due to nausea, vomiting, dizziness, and drowsiness. The 4th patient withdrew during the 4th week of treatment with oxycodone and pregabalin at 300 mg/day due to dizziness, drowsiness, and hallucination. One patient in the pregabalin/placebo group discontinued due to lack of treatment efficacy.
Discussion This study was designed to evaluate the efficacy, safety, and tolerability of a combination of a low, fixed, daily dose of oxycodone at 10 mg/day with pregabalin, relative to placebo with pregabalin, in the treatment of PHN and PDN. The primary efficacy measure demonstrated that there was no significant difference when a low dose of oxycodone 10 mg/day was added to pregabalin. Although a low dose of oxycodone at 10 mg/day has been shown to be effective in the treatment of nociceptive pain when combined with other analgesics,25,33 there was no apparent additional benefit when administered in combination with pregabalin for the treatment of neuropathic pain in the present study.
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Pregabalin and Oxycodone, Clinical Trial in PHN and PDN
Table 2.
Summary of Mean Change in Efficacy Measures from Baseline to Endpoint PREGABALIN/OXYCODONE
PREGABALIN/PLACEBO
MEAN COMPARISON
MEASURES
N
MEAN
SD
N
MEAN
SD
Pain score Sleep interference score Neuropathic pain scale Intense Sharp Hot Dull Cold Sensitive Itchy Unpleasant Deep Surface NPS 10 Short form-36 Physical function Role physical Bodily pain General health Vitality Social function Role emotional Mental health Physical summary Mental summary Profile of Mood States Tension Anxiety Depression Dejection Anger Hostility Vigor Activity Fatigue Inertia Confusion Bewilderment Total Mood Disturbances TMTB Time to complete Number of error
26 26
3.59 2.82
2.35 3.21
29 29
4.03 3.93
2.33 2.7
DIFFERENCE .44 .12
P VALUE
26
2.46 2 1.92 1.69 .57 2.15 1.65 2.03 1.34 2.15 18
3.24 3.44 3.9 2.63 2.48 3.19 2.27 3.07 3.27 3.3 23.07
29
3 2.41 2.48 2.31 0.41 1.82 .89 2.41 2.24 2.13 20.13
2.87 3.75 3.51 3.47 1.59 2.81 2.25 2.41 3.05 2.92 18.66
.54 .41 .56 .62 .16 .33 .76 .38 .9 .02 2.13
.89 .04* .005* .53 .03* .17 .78 .16 .51 .24 .25
23
6.73 18.47 13.43 7.47 7.39 12.43 12.43 6.6 4.39 3.86
17.29 51.24 18.6 19.82 22.45 27.77 47.19 18.66 8.78 11.16
28
7.14 24.1 18 2 12.32 54.75 20.82 16.35 3.1 7.82
14.74 43.29 21.16 10.09 18.07 34.85 47.28 13.46 7.05 9.06
.41 5.63 4.57 5.47 4.93 42.32 8.39 9.75 1.29 3.96
.74 .09 .29 .04* .06 .81 .38 .004* .83 .03*
24
2.62 3.12 1.58 2.87 2.16 1.04 13.37
6.49 8.17 5.57 6.32 6.23 3.54 30.49
28
3.28 2.67 3.46 3.07 3.14 .57 16.25
3.44 6.56 3.44 5.59 4.47 3.50 15.87
.66 .45 1.88 .2 .98 .47 2.88
.65 .13 .56 .21 .95 .09 .13
21
.19 .19
1.69 1.16
24
.16 .33
1.2 2.03
.03 .14
.05 .72
.07 .19
Abbreviations: N, number of patients; SD, standard deviation; NPS, neuropathic pain scale; TMTB, trail making test B. NOTE. Difference means comparison between pregabalin/oxycodone and pregabalin/placebo in the mean change from baseline (visit 2) to endpoint (visit 4) and P value was based on analysis of covariance using baseline score as a covariate. *P value is significant.
In previous studies, the effective doses of pregabalin in the treatment of neuropathic pain have been found to be between 300 and 600 mg/day17,27,28 whereas at 75 mg/day, there was no demonstrated benefit over the placebo.17 The findings from the present preliminary study suggest the possibility of a benefit of combining a low dose of oxycodone with lower doses of pregabalin in the treatment of PHN and PDN in the clinical setting. This remains to be examined in future investigations in larger clinical trials conducted over a longer period. As the present study used forced titration to the maximum tolerated dose or the maximum dose of pregabalin (600 mg/day), the proportion of patients who achieved treatment success and a pain reduction of $50% at higher doses of pregabalin in the pregabalin/placebo group may have contributed to the overall similar levels of treatment efficacy found between the 2 groups in this study.
Furthermore, the patient population in this study comprised patients with either PHN or PDN. The mean duration of PDN in the pregabalin/oxycodone group was longer at 4.5 years compared with 2.9 years for patients in the pregabalin/placebo group. This may have reduced the overall efficacy of treatment in the pregabalin/oxycodone group relative to the pregabalin/placebo group, as patients with long-term PDN may potentially have more advanced neuropathy that is less responsive to treatment with most agents.18 Moreover, a greater proportion of female patients (52%) in the pregabalin/placebo group than the pregabalin/oxycodone group (33%) may have potentially affected the efficacy of a treatment in this study, as female gender is associated with a stronger placebo effect compared with male patients.11 This may have contributed to the strong placebo effect (35%) in the pregabalin/placebo group. Despite the use of a block randomization design, the present
Zin et al
469
Adverse Events with an Incidence Greater Than 5%
80
Table 3. Pgb/oxy
65.6
Pgb/pla
60
55.2 53.8
% of Patients
46.2 41.1 34.5 23.1 20
0
Oxy/pla
PGB/PLA N = 30
57.7
50.0
40
PGB/OXY N = 27
62.1
Pgb 150mg/d Pgb 600mg/d Pgb 75mg/d Pgb 300mg/d
Figure 3. Responder rates (based on $50% pain reduction from baseline to endpoint) at each different dosage level. Pgb/oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo; week 1, baseline; week 2, oxycodone/placebo; week 3, pregabalin 75 mg/day and oxycodone/placebo; week 4, pregabalin 150 mg/day and oxycodone/placebo; week 5, pregabalin 300 mg/ day and oxycodone/placebo; week 6, pregabalin 600 mg/day and oxycodone/placebo
study still resulted in an imbalance between the 2 groups in the above-mentioned patient characteristics. Given the preliminary nature of the present study and the high response rate observed in the group administered placebo in combination with pregabalin, this made it difficult to assess whether or not there was a significant effect of oxycodone relative to placebo. Thus, the results of the primary efficacy outcome of this study would best be used to design future studies to more thoroughly assess the effectiveness of this combination of analgesic agents. Future studies involving titration of patients to efficacy rather than forced titration to the maximum dose of pregabalin at 600 mg/day would have an improved ability to detect significant differences between the placebo/pregabalin and oxycodone/pregabalin treatment groups at the lower doses of pregabalin. This has been shown in the present study such that there was a nonsignificant trend for a low dose of oxycodone at 10 mg/day, combined with lower doses of pregabalin at 75 and 150 mg/day, to produce a treatment success of at least a 2-cm drop and <4 cm on the VAS, in a greater proportion of patients in the pregabalin/oxycodone group compared with patients in the pregabalin/placebo group.The secondary efficacy measures including the NPS, SF-36, and POMS were improved in both treatment groups at the end of study. These secondary efficacy measures demonstrated similar levels of efficacy between the 2 treatment groups. The occurrence of adverse events was comparable between the pregabalin/oxycodone (89%) and the pregabalin/placebo group (80%). Only constipation and itch were reported to be significantly higher in the pregabalin/oxycodone group than in the pregabalin/placebo group. These adverse events may be caused by oxycodone, as they are commonly seen with all opioid analge-
ADVERSE EVENTS
N
(%)
N
(%)
P VALUEz
Dizziness Drowsiness Constipation Nausea Headache Tiredness Itch Vomiting Sleepiness Visual disturbances Hallucination Imbalance Sweating Tremor Diarrhea Peripheral edema
22 19 18 13 6 6 5 3 3 3 2 2 2 2 1 1
82 70 67 48 22 22 19 11 11 11 7 7 7 7 4 4
17 14 8 8 6 6 0 2 0 2 0 2 0 1 3 3
57 47 27 27 20 20 0 7 0 7 0 7 0 3 10 10
.052 .107 .0035* .108 1 1 .019* .659 .1 .659 .219 1 .219 .598 .613 .613
Abbreviations: Pgb/oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo. *P < .05. zFisher’s exact test.
sics. Nevertheless, the present study showed that the occurrence of opioid-related adverse events was lower compared with a previous study that used higher doses of oxycodone (20–120 mg/day).10 In the previous study, constipation, somnolence, nausea, dizziness, and vomiting were shown to be significantly higher in the oxycodone group compared with the placebo group.10 Most of the adverse events that occurred in this study were well tolerated and rated as mild in intensity, regardless of the treatment group. There were no serious drug-related adverse events reported. Four patients in the pregabalin/oxycodone group withdrew from the study, 3 of whom withdrew during the first week of the study while taking oxycodone alone. This suggests that the intolerable adverse events which occurred in this study were due to oxycodone alone and that the use of a low dose of oxycodone (10 mg/day) in combination with pregabalin does not cause synergistic or additive adverse events. The strengths of the present study include the use of a randomized double-blind design to limit possible bias, use of multiple measures to assess all aspects of efficacy and safety, and an adequate dose range for the assessment of a dose-response relationship between the combination of pregabalin/oxycodone relative to pregabalin alone. Limitations of the present study include small sample size making it difficult to draw firm conclusions. However, the present study findings provide a solid basis for the design of a larger future study to further assess the efficacy of a combination of oxycodone and pregabalin in the treatment of PHN and PDN. The present 6-week study was designed to mimic the treatment paradigm used in clinical practice and not intended to determine whether the analgesic effects produced by a combination
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Pregabalin and Oxycodone, Clinical Trial in PHN and PDN
of oxycodone and pregabalin are long lasting. Another limitation of the present study includes the use of pregabalin in an open-label forced-titration dosing regimen such that patients and investigators were aware of the increasing dose of pregabalin. This may have contributed to the magnitude of the placebo effect observed in this study such that greater pain relief with higher pregaba-
lin dosages resulted from knowledge of dosage escalation and not to the pharmacologic effects of the dosage increases. In summary, this preliminary study has shown that coadministration of a low-dose oxycodone at 10 mg/day with pregabalin did not enhance pregabalin efficacy in patients with PHN or PDN.
References
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1. Baron R: Mechanisms of disease: neuropathic pain - a clinical perspective. Nat Clin Pract Neurol 2:95-106, 2006 2. Belliotti TR, Capiris T, Ekhato IV, Kinsora JJ, Field MJ, Heffner TG, Meltzer LT, Schwarz JB, Taylor CP, Thorpe AJ, Vartanian MG, Wise LD, Zhi-Su T, Weber ML, Wustrow DJ: Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein. J Med Chem 48: 2294-2307, 2005 3. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Catherine Bushnell M, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weisntein SM: Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60:1524-1534, 2003 4. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EJ, Loeser JD, Miaskowski C, Nurmiko TJ, Portenoy RK, Rice ASC, Stacey BR, Treede RD, Turk DC, Wallace MS: Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 132: 237-251, 2007 5. Farrar JT, Young JP, LaMoreaux L, Werth JL, Poole RM: Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94:149-158, 2001 6. Fazen LE, Ringkamp M: The pathophysiology of neuropathic pain: A review of current research and hypotheses. Neurosurg Q 17:245-262, 2007 7. Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, Duffy S, Clusmann H, Gothert M: Inhibition of neuronal Ca21 influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 42:229-236, 2002
14. Harden RN: Chronic neuropathic pain - mechanisms, diagnosis, and treatment. Neurologist 11:111-122, 2005 15. Jensen MP, Dworkin RH, Gammitoni AR, Olaleye DO, Oleka N, Galer BS: Assessment of pain quality in chronic neuropathic and nociceptive pain clinical trials with the Neuropathic Pain Scale. J Pain 6:98-106, 2005 16. Lee TMC, Cheung CCY, Chan JKP, Chan CCH: Trail making across languages. J Clin Exp Neuropsychol 22:772-778, 2000 17. Lesser H, Sharma U, LaMoreaux L, Poole RM: Pregabalin relieves symptoms of painful diabetic neuropathy: A randomized controlled trial. Neurology 63:2104-2110, 2004 18. Low PA, Dotson RM: Symptomatic treatment of painful neuropathy. JAMA 280:1863-1864, 1998 19. Max M: Neuropathic pain syndromes, in Max M, Portenoy R, Laska E, (eds): Advances in pain research and therapy, Vol 18. New York, NY, Raven Press Ltd, 1991, pp 193-219 20. McNair DM, Lorr M, Droppleman LF: Profile of mood states (POMS) manual. San Diego, CA, Educational and Industrial Testing Service, 1992. pp 1-28 21. Merskey H, Bogduk N: Classification of Chronic Pain, (2nd ed.) Seattle. WA, IASP Press, 1994. p 394 22. Namaka M, Gramlich CR, Ruhlen D, Melanson M, Sutton I, Major J: A treatment algorithm for neuropathic pain. Clin Ther 26:951-979, 2004 23. Ostelo RW, de Vet HC: Clinically important outcomes in low back pain. Best Pract Res Clin Rheumatol 19:593-607, 2005
8. Galer BS, Jensen MP: Development and preliminary validation of a pain measure specific to neuropathic pain: The Neuropathic Pain Scale. Neurology 48:332-338, 1997
24. Pappagallo M, Haldey EJ: Pharmacological management of postherpetic neuralgia. CNS Drugs 17:771-780, 2003
9. Gilron I, Bailey JM, Tu DS, Holden RR, Weaver DF, Houlden RL: Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 352:1324-1334, 2005
25. Reuben SS, Connelly NR, Maciolek H: Postoperative analgesia with controlled-release oxycodone for outpatient anterior cruciate ligament surgery. Anesth Analg 88: 1286-1291, 1999
10. Gimbel JS, Richards P, Portenoy RK: Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial. Neurology 60:927-934, 2003
26. Rice AS, Maton S: Gabapentin in postherpetic neuralgia: A randomised, double blind, placebo controlled study. Pain 94:215-224, 2001
11. Grosskopf J, Mazzola J, Wan Y, Hopwood M: A randomized, placebo-controlled study of oxcarbazepine in painful diabetic neuropathy. Acta Neurol Scand 114: 177-180, 2006
27. Richter RW, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp LE: Relief of painful diabetic peripheral neuropathy with pregabalin: A randomized, placebocontrolled trial. J Pain 6:253-260, 2005
12. Hanna M, O’Brien C, Wilson MC: Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain 12: 804-813, 2008
28. Rosenstock J, Michael TB, LaMoreaux L, Sharma U: Pregabalin for the treatment of painful diabetic peripheral neuropathy: A double-blind, placebo-controlled trial. Pain 110:628-638, 2004
Zin et al 29. Rowbotham M, Harden N, Stacey B, Berstein P, MagnusMiller L: Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA 280: 1837-1842, 1998 30. Salaffi F, Stancati A, Silvestri CA, Ciapetti A, Grassi W: Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain 8:283-291, 2004 31. Schmader KE: Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 18:350-354, 2002
471 34. Ware JE, Sherbourne CD: The Mos 36-Item Short-Form Health Survey (Sf-36) .1. Conceptual-framework and Item selection. Med Care 30:473-483, 1992 35. Watson CPN, Babul N: Efficacy of oxycodone in neuropathic pain - a randomized trial in postherpetic neuralgia. Neurology 50:1837-1841, 1998 36. Watson CPN, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J: Controlled-release oxycodone relieves neuropathic pain: A randomized controlled trial in painful diabetic neuropathy. Pain 105:71-78, 2003
32. Spreen O, Strauss E: A compendium of neuropsychological tests, (2nd ed.) New York. NY, Oxford University Press, 1998. pp 533-547
37. Woolf CJ, Decosterd I: Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain 6:S141-S147, 1999
33. Sunshine A, Olson NZ, Colon A, Rivera J, Kaiko RF, Fitzmartin RD, Reder RF, Goldenheim PD: Analgesic efficacy of controlled-release oxycodone in postoperative pain. J Clin Pharmacol 36:595-603, 1996
38. Zin CS, Nissen LM, Smith MT, O’Callaghan JP, Moore BJ: An update on the pharmacological management of postherpetic neuralgia and painful diabetic neuropathy. CNS Drugs 22:417-442, 2008
A Randomized, Controlled Trial of Oxycodone Versus Placebo in Patients With PostHerpetic Neuralgia and Painful Diabetic Neuropathy Treated With Pregabalin Che S. Zin,* Lisa M. Nissen,* James P. O’Callaghan,y Stephen B. Duffull,*,x Maree T. Smith,*,z and Brendan J. Moore*,y * The University of Queensland, School of Pharmacy, St Lucia Campus, QLD 4072, Australia. y Greenslopes Private Hospital, QLD 4120, Australia. z Centre for Integrated Preclinical Drug Development, St Lucia Campus, QLD 4072, Australia. x University of Otago, School of Pharmacy, Dunedin, 9054, New Zealand.
Abstract: The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/ day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the painintensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain. Perspective: Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in 40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin. ª 2010 by the American Pain Society Key words: Pregabalin, oxycodone, postherpetic neuralgia, painful diabetic neuropathy.
N
europathic pain is the result of a primary lesion or dysfunction in any part of the nervous system.21 Neuropathic pain is often classified into 2 groups, central and peripheral.6 Peripheral neuropathic pain presents commonly in clinical practice and 2 of its most prevalent types are postherpetic neuralgia (PHN) and Received December 17, 2008; Revised August 7, 2009; Accepted September 1, 2009. Supported by a research grant from The Gallipoli Research Trust Foundation, Greenslopes Private Hospital. C.S.Z. was supported by a PhD scholarship funded by the Malaysian Government. Address reprint requests to Dr Lisa Nissen, The University of Queensland, Room 3308C, Steele Building, School of Pharmacy, St Lucia Campus, Brisbane, Australia, 4072. E-mail: [email protected] 1526-5900/$36.00 ª 2010 by the American Pain Society doi:10.1016/j.jpain.2009.09.003
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painful diabetic neuropathy (PDN).13,14,31 PHN is a serious complication of shingles or herpes zoster infection while PDN is a common long-term complication of diabetes mellitus. Although currently available treatments have been shown to be effective for the treatment of neuropathic pain, dose-limiting side effects and drug interactions limit their usefulness in some patients. It is estimated that 40 to 60% of patients experience some degree of pain relief with currently available treatments, leaving the remainder with unremitting pain.38 Over the last 15 years, the multiplicity of underlying mechanisms contributing to the development and maintenance of neuropathic pain have become clearer.22,37 With multiple contributing mechanisms, the administration of drug treatments in combination, each producing
Zin et al pain relief through distinctly different mechanisms, may have the potential to produce superior patient outcomes relative to large doses of individual drugs administered alone.1 This suggested approach has the potential to improve efficacy outcomes and reduce adverse effects in patients who achieve only partial pain relief from a single agent or who experience dose-limiting side effects from large doses of a single antineuropathic agent.3 Based on the efficacy of currently available treatments for neuropathic pain, combinations of 2 or more drugs from the following treatments groups—gabapentin/pregabalin, duloxetine/venlafaxine, lidocaine patch 5%, opioid analgesics (oxycodone and morphine), and tricyclic antidepressants (TCAs)—are worthy of future clinical-trial evaluation.4 Preclinical studies indicate that spontaneous ongoing pain symptoms secondary to central sensitization of the dorsal horn of the spinal cord may be alleviated by drugs acting to block calcium (Ca21) channels or sodium (Na1) channels, or by boosting descending inhibitory mechanisms.1 Thus, drugs such as gabapentin and pregabalin that are thought to produce pain relief through inhibition of presynaptic calcium channels2,7 may produce additive or possibly synergistic benefit when combined with an opioid, or with an antidepressant.3,24 The combination of morphine and gabapentin has been shown to be superior to morphine alone, gabapentin alone or placebo, in relieving pain and improving daily functions in patients with PHN or PDN.9 These benefits were observed at lower doses with the combination of drug treatment than for a single therapy. Another combination study in patients with PDN demonstrated that the combination of gabapentin and oxycodone produced greater treatment effects than gabapentin/ placebo.12 Thus far, clinical trials evaluating the analgesic efficacy of a combination of pregabalin and opioid have not been published. Pregabalin has linear pharmacokinetics and a faster onset of action compared with gabapentin which make pregabalin a superior option for use in analgesic combination studies.12 Furthermore, as pregabalin requires twice-daily dosing, rather than the thrice-daily dosing for gabapentin, pregabalin’s longer interdosing interval has the potential to improve patient compliance.4 Although oxycodone has been shown to have efficacy for the treatment of PHN or PDN in a number of studies, dosages in the range of 20 to 120 mg/day are associated with a high frequency of unwanted opioid-related side effects.10,35,36 Hence, this study was designed to assess whether or not administration of a low dose of oxycodone (10 mg/day) administered in combination with pregabalin would enhance the pain-relieving efficacy of pregabalin for the symptomatic relief of patients with either PHN or PDN. For the treatment of nociceptive pain, this low dose of oxycodone at 10 mg/day has been shown to be beneficial when combined with other analgesics such as paracetamol and NSAIDs.25,33 Similar combination studies are lacking in neuropathic pain.
463
Methods Study Design This study was a randomized, double-blind, placebocontrolled, parallel-group, single-center clinical trial to evaluate the efficacy and safety of a low fixed dose of oxycodone (10 mg/day) or placebo in combination with pregabalin, administered according to an openlabel forced-titration dosing regimen in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). This study was conducted at Greenslopes Private Hospital (GPH), Brisbane, Australia. Patients were recruited through a number of methods including advertisements in local, state, and national newspapers, diabetes Australia (Queensland) magazines, faxouts/newsletters to local general practitioners, and referral to the GPH Pain Clinic. Recruitment was undertaken from July 2006 until December 2007. The study was approved by the Human Research Ethics Committee of GPH and from the Medical Research Ethics Committee of The University of Queensland. Inclusion criteria included: 1) male or female outpatients aged $18 years; 2) established diagnosis of PHN of at least 3 months’ duration but no more than 5 years’ duration after crusting of the last lesion; 3) established diagnosis of PDN for 1 to 5 years; 4) a pain-intensity score of at least 4 cm on a 10-cm visual analogue scale (VAS) for the past 24 hours; 5) no coexisting moderate to severe pain that could potentially confound the assessment or self-evaluation of neuropathic pain due to PHN or PDN; 6) no evidence of moderate or severe renal impairment, ie, creatinine clearance must be >30 mL/min (calculated using Cockcroft-Gault equation); and 7) female patients had to be nonpregnant, nonlactating and either postmenopausal, surgically sterilized, or using an appropriate method of contraception. Exclusion criteria included: 1) known allergic reaction or contraindicated to pregabalin or oxycodone; 2) had other unstable medical conditions such as myocardial infarction, cardiac conduction defect, severe pulmonary disease, and severe depression; 3) taking monoamine oxidase inhibitors; and 4) history of substance abuse involving agents such as opioids and alcohol.
Baseline This study involved 4 clinic visits over a period of 6 weeks. During visit 1, patients were assessed for compliance with the study inclusion criteria, a full medical history was obtained, and physical examination performed. Patients who met all of the inclusion criteria and none of the exclusion criteria, and who gave written informed consent, were recruited to enter a 7-day studywashout period. Medications that might possibly affect painful symptoms including opioid analgesics, anticonvulsants (eg, gabapentin, pregabalin, sodium valproate, lamotrigine), tricyclic antidepressants, capsaicin, benzodiazepines, and skeletal muscle relaxants were gradually withdrawn during the study-washout period. Patients were permitted to continue taking paracetamol as rescue medication,
464 aspirin (up to 325 mg/day) for cardiovascular prophylaxis, and serotonin selective reuptake inhibitors for treatment of depression. During baseline and treatment phases, each day upon awakening patients recorded pain-intensity scores evaluated for the previous 24 hours on a 10-cm VAS (0 = no pain, 10 = worst possible pain) in their study diary. The question about the pain intensity was ‘‘how do you feel today?’’ It was explained to patients that they were required to rate their pain intensity in the past 24 hours and this was reinforced to patients during telephone calls from study investigators.
Treatments To be eligible for entry into the main study, patients had to have recorded pain-intensity scores in their study diary for at least 4 out of the previous 7 days of the studywashout period when they returned to the study center for visit 2. Additionally, patients had to continue to meet all of the inclusion criteria and none of the exclusion criteria. During visit 2, patients were randomized to receive oxycodone mixture 2.5 mL (2 mg/mL) or placebo mixture 2.5 mL twice a day for 1 week. Patients were assigned to 1 of 2 treatment groups using a computer-generated randomization number in block sizes of 10. The randomization sequence list was controlled independently by the clinical pharmacist at GPH. All of the characteristics (appearance, taste, and method of administration) of the oxycodone and placebo mixture were identical to ensure that study blinding was maintained. The oxycodone and placebo mixtures were prepared by the Central Pharmacy of the Royal Brisbane and Women’s Hospital, and the pregabalin (Lyrica) marketed by Pfizer, was purchased from commercial sources. All the study medications were supplied to patients by the clinical-trial pharmacist at the GPH. After a 7-day treatment period with either oxycodone alone or placebo alone, patients returned to the GPH pain clinic for visit 3, and they were then started on pregabalin while continuing with the same dosage of either oxycodone mixture or placebo mixture for 4 weeks. The starting dose for pregabalin was 75 mg once daily, which was titrated at weekly intervals to 75 mg twice daily (bd), 150 mg bd, then to a maximum dose of 300 mg bd. Dosage escalation was terminated once the patient achieved the maximum dosage of 600 mg/day or the maximum tolerated dose (the immediate dose level less than the dose which caused intolerable side effects). Patients then remained on this dose (pregabalin plus oxycodone or placebo mixture) for a further 7-day period to complete the study. Accordingly, patients who tolerated the maximum dose of pregabalin or the maximum tolerated dose at lower doses of pregabalin, completed the study in less than 6 weeks. After taking the final study medication for 7 days, patients returned to the study centre for a final review (visit 4). Final assessment, including a full medical and physical examination, were performed. The dose level that produced a clinical benefit (considered to be at least a 2 cm drop in VAS pain scores and
Pregabalin and Oxycodone, Clinical Trial in PHN and PDN a VAS pain score <4 cm) was recorded for the primary efficacy measure. Side effects (dizziness, drowsiness, nausea, vomiting, and constipation) that occurred at this dose level were also recorded. In addition, the VAS score and side effects were recorded at each dose level up to the maximum dose or maximum tolerated dose. Patients were allowed to use paracetamol as their breakthrough medication during the study period. During the trial, the study investigator made regular telephone calls to patients to monitor their well-being, to ensure that the patients were taking their study medication, and that they were completing the study diary appropriately. The titration of pregabalin medication was performed via telephone consultation between a study investigator and the patient.
Efficacy Measures Primary Efficacy Outcome Measure The primary efficacy measure was at least a 2-cm drop in the pain-intensity score23 and a pain-intensity score of less than 4 cm measured by VAS from baseline, following pregabalin dosage escalation. This was evaluated from each patient’s study diary and was considered as the criteria for a treatment success for this study. The baseline pain score for this study is defined as the mean of the last 4 pain-diary entries prior to initiation of oral treatment with either the oxycodone or the placebo mixture. The VAS pain scores during the pregabalin dosage escalation were obtained by averaging the 4 daily pain-intensity scores recorded prior to forced titration of the pregabalin dose to the next level. Supplementary measures for primary efficacy included weekly pain score and responder rates (based on $50% pain reduction from baseline) evaluated from each patient’s study diary. The calculation for responder rates was similar to the calculation for the primary efficacy measure. The mean pain scores had to decrease $50% from the baseline following the pregabalin dose escalation for the patient to be considered as a responder.
Secondary Efficacy Outcome Measures Secondary outcome measures were evaluated from questionnaires completed during the study.
Sleep Interference Score Sleep interference was assessed using a 10-cm VAS with the delimiters ‘‘did not interfere’’ and ‘‘cannot sleep at all due to pain’’.19 Sleep interference was evaluated from each patient’s study diary entries by comparing the degree of sleep interference from baseline to the study endpoint.
Neuropathic Pain Scale (NPS) The NPS8 is specifically designed for measuring pain qualities associated with neuropathic pain conditions. This instrument has 10 questions that consist of 8 descriptors for pain conditions, 1 descriptor for pain intensity, and 1 descriptor for unpleasantness.15 The descriptors of the pain conditions include: ‘‘sharp’’, ‘‘hot’’, ‘‘dull’’,
Zin et al ‘‘cold’’, ‘‘sensitive’’, ‘‘itchy’’, ‘‘deep’’, and ‘‘surface’’. NPS was administered at every study visit.
465 15
The
Short-Form 36 (SF 36) The SF-3634 is a self-administered questionnaire consisting of 8 health concepts: 1) limitation in physical activities because of health problems (physical functioning); 2) limitations in social activities because of physical or emotional problems (social functioning); 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health; 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. This SF-36 was administered at visit 1, visit 2 and visit 4.
Profile of Mood States (POMS) The POMS20 is a self-administered instrument and is widely used to assess changes in mood in many neuropathic pain trials.17,27,28 The POMS consists of 65 questions measuring 6 different subscales: 1) tensionanxiety; 2) depression-dejection; 3) anger-hostility; 4) fatigue-inertia; 5) confusion-bewilderment; 6) vigoractivity. The POMS was administered at visits 1, 2, and 4.
Trail Making Test B (TMTB) The TMTB32 was used for the assessment of cognitive performance. The TMTB requires the patient to connect letters and numbers in alternating order (1-A-2-B-3-C, etc) in as little time as possible.16 This test was administered at visits 1, 2, and 4.
Patient Global Impression of Change (PGIC) The PGIC5 was utilized to assess global improvement based on patient rating. The PGIC consists of 7 descriptors (‘‘very much improved’’, ‘‘much improved’’, ‘‘minimally improved’’, ‘‘no change’’, ‘‘minimally worse’’, ‘‘much worse,’’ and ‘‘very much worse’’).5,30 The PGIC was administered at the end of the study.
Clinician Global Impression of Change (CGIC) The CGIC5 was utilized to assess global improvement based on clinician rating. The CGIC consists of 7 descriptors (‘‘very much improved’’, ‘‘much improved’’, ‘‘minimally improved’’, ‘‘no change’’, ‘‘minimally worse’’, ‘‘much worse,’’ and ‘‘very much worse’’).5,30 The CGIC was administered at the end of the study. Safety measures were based on the frequency and severity of adverse events which were assessed based upon the entries in the study diary and during openended questioning by the investigator at each study visit.
Power Analysis The power of this study was assessed using clinical-trial simulation techniques. Using this technique, a virtual clinical trial was created and outcomes simulated for 200 replications of the virtual trial. The power was calculated as the proportion of times that replications of the trial showed a difference between the 2 treatment arms. The virtual trial was designed to have similar fea-
tures to the actual clinical trial conducted here, ie, was a parallel-design dose-escalation study. All simulations were performed using MATLAB (The MathCorks Inc, Natick, MA). These simulations indicated that enrolling a total of 50 patients over the 2 treatment groups, ie, 25 patients per arm but allowing replacement for dropouts, would provide a power of approximately 80% to detect a clinically significant difference between the 2 treatment arms with an alpha error (2a) of 5%. A clinically significant difference was defined as both a drop of 2 cm on the VAS as well as a final VAS score of less than 4 cm. The baseline VAS score was 7 cm (62 cm) [mean 6 SD], with a minimum VAS score of 4 cm. The expected mean change in VAS score from pregabalin alone was a reduction in 2 cm and for the combination of pregabalin and oxycodone a reduction of 3.5 cm. The virtual clinical trial included dropouts due to lack of tolerability in a dosedependent manner with dropouts reaching 20% with daily doses of pregabalin approaching 300 mg. These dropouts are based on the reports of gabapentin studies26,29 in the treatment of postherpetic neuralgia and an assumption that the equipotent dose ratio of pregabalin and gabapentin was approximately 6. Based on this and the possibility of random dropouts, then recruitment of 63 patients would be sufficient to ensure that 50 patients completed the study.
Statistical Methodology All analyses were conducted on an intention-to-treat basis. All randomized patients were included in the safety analyses and all randomized patients with baseline and at least 1 postbaseline efficacy assessment were included in the efficacy evaluations. Missing observations due to discontinuation of treatment were extrapolated by carrying forward the mean of the last 4 observations (LOCF) immediately before discontinuation through to the final visit. All testing was 2-sided and was performed using Number Cruncher Statistical Software (NCSS, Kaysville, UT, 2004). The percentage of patients who obtained at least a 2-cm drop in the VAS score relative to baseline and <4 cm on the VAS pain score (primary efficacy measure), and who achieved $50% pain reduction, gave the responder rates of the 2 treatment groups, and these were compared by the Chi Squared test. Comparison between treatments in the change from baseline in mean pain scores, mean sleep scores, NPS, SF-36 domains, POMS total scores and TMTB were analyzed using an analysis of covariance (ANCOVA) model. The fixed terms of this model were treatment, type of pain, and baseline mean score as a covariate. The data for POMS were not normally distributed, and so they were normalized using rank transformation. PGIC and CGIC were analyzed using the Cochrane Mantel Haenszel (CMH) test. Safety analyses were conducted for all randomized patients who received at least 1 dose of study medication (safety population). The number of each type of adverse event was analyzed using descriptive statistical methods.
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Pregabalin and Oxycodone, Clinical Trial in PHN and PDN Screened N=134 Did not meet criteria N=38 Did not tolerate washout period N=5 Other/administrative N=29 Randomized N=62
Oxycodone N=29
Placebo N=33
Total withdrawn N=5 (Adverse events N=3 Other/administrative N=2)
Total withdrawn N=4 (Lack of efficacy N=1 Other/administrative N=3)
Pregabalin/oxycodone N=24
Pregabalin/placebo N=29
Total withdrawn N=1 (Adverse events N=1)
Total withdrawn N=1 (Lack of compliance N=1)
Completed N=23
Completed N=28
Figure 1. A consort diagram.
Results Patient Disposition A total of 134 patients were screened with 62 patients randomized to receive treatment (Fig 1). Of these 62 patients, 29 received pregabalin/oxycodone and 33 received pregabalin/placebo. In the pregabalin/oxycodone group, 2 patients withdrew before taking any study medication due to administrative issues and were not included in the analysis. In the pregabalin/placebo group, 3 withdrawals were not included in the analysis as these patients withdrew before they started taking study medication due to administrative issues. Overall, 82% (51/62) of total randomized patients completed the entire study, with 79% (23/29) of patients in the pregabalin/oxycodone group and 85% (28/33) of patients in the pregabalin/placebo group.
Patient Demographics Patient baseline characteristics are summarized in Table 1. There were more males than females in the pregabalin/oxycodone group compared with the pregabalin/placebo group. Additionally, patients in the pregabalin/oxycodone group reported a slightly shorter duration of PHN, but longer duration of PDN, compared with patients in the pregabalin/placebo group. Importantly, the mean (6SEM) baseline pain scores were similar (P > .05) in the pregabalin/oxycodone group (6.85 6 .30) compared with the pregabalin/placebo group (6.73 6 .29).
Primary Efficacy Measure There was no significant difference in the overall proportion of patients who achieved at least a 2-cm drop in
Patients Demographic and Baseline Characteristics
Table 1.
CHARACTERISTICS
PGB/OXY (N = 29)
Sex Male n (%) 19 (65.5) Female n (%) 10 (33.4) Age Mean 6 SD 70.27 6 11.49 Range 50–91 Race White n (%) 27 (93.1%) Other n (%) 2 (6.8%) Weight, kg 83.9 6 21.55 mean 6 SD Height, cm 171.28 6 9.06 mean 6 SD Disease history PHN n (%) 15 (51.7) Duration of PHN-year, 1.62 6 1.22 mean 6 SD PDN n (%) 14 (48.2) Duration of PDN-year, 4.5 6 3.71 mean 6 SD Baseline pain score, 6.85 6 .30 mean 6 SEM
PGB/PLA (N = 33)
TOTAL PATIENTS (N = 62)
16 (48.5) 17 (51.5)
35 (56.4) 27 (43.5)
66.8 6 11.7 45–87 33 (100) 0 (0) 82.2 6 19.33
60 (96.7) 2 (3.2)
167 6 10.82
17 (51.5) 2.76 6 1.8
32 (51.6)
16 (48.4) 2.88 6 1.75
30 (48.3)
6.73 6 .29
Abbreviations: Pgb/Oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo; n, number of patients; PHN, post-herpetic neuralgia; PDN, painful diabetic neuropathy.
the pain-intensity score and a pain-intensity score of less than 4 cm on the VAS in the pregabalin/oxycodone (69%) and pregabalin/placebo (76%) groups (P = .581, chi squared test). Analysis at different dose levels showed that a greater proportion of patients in the pregabalin/ oxycodone group achieved a treatment success at lower doses of pregabalin (75 and 150 mg/day [58% and 65%]) compared with patients in the pregabalin/placebo group (52% and 62%), but this did not reach statistical significance (P > .05, chi squared test) (Fig 2). A majority of patients in the pregabalin/placebo group achieved treatment success at higher doses of pregabalin (300 and 600 mg/day). As doses were titrated to the maximum tolerated dose, it was shown that at pregabalin 600 mg/day, there were no additional new patients who obtained treatment success either for the pregabalin/ oxycodone group or for the pregabalin/placebo group (Fig2).
Supplemental Measures of Primary Efficacy Weekly mean pain scores were improved in both groups at the study endpoint. The results showed an overall decrease of 3.59 (52.4%) for the pregabalin/oxycodone group and 4.02 (59.7%) for the pregabalin/placebo group. There was no significant difference in pain reduction between the 2 groups (P = .074, ANCOVA) (Table 2). Responder rates based on $50% pain reduction from baseline to endpoint were not significantly different
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80
Pgb/oxy
75.9
Pgb/pla
69.2
75.9 69.2
65.4 62.0 57.7
60
% of Patients
51.7
40
34.5 30.8
Safety Measures
20
0
Seventeen and thirty percent of patients in the pregabalin/oxycodone group rated themselves as very much and much improved on the PGIC scale compared with 21% and 54% of patients in the pregabalin/placebo group. The differences between the groups were not statistically significant (P = .868, CMH). The CGIC findings also showed a similar trend to the PGIC scale and there was no significant difference between the 2 groups (P = .866, CMH).
Oxy/pla
Pgb 150 mg/d Pgb 75 mg/d
Pgb 600 mg/d
Pgb 300 mg/d
Figure 2. Treatment success at different dosage levels. Pgb/oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo; week 1, baseline; week 2, oxycodone/placebo; week 3, pregabalin 75 mg/day and oxycodone/placebo; week 4, pregabalin 150 mg/ day and oxycodone/placebo; week 5, pregabalin 300 mg/day and oxycodone/placebo; week 6, pregabalin 600 mg/day and oxycodone/placebo. between the 2 treatment groups (P = .551, chi squared test). Fifty-eight percent (15/26) of patients treated with pregabalin/oxycodone experienced $50% pain reduction, compared with 66% (19/29) of patients treated with pregabalin/placebo (Fig 3).
Secondary Efficacy Measures Both treatment groups were improved in all secondary efficacy measures at the end of the study. There were no significant differences in all secondary efficacy measures except in certain domains of the NPS and the SF-36 (Table 2). For the NPS, the pregabalin/oxycodone group had significant improvement in cold pain (P = .035, ANCOVA), while the pregabalin/placebo group demonstrated significant improvement in sharp (P = .042, ANCOVA) and hot pain (P = .005, ANCOVA). For the SF-36, patients in the pregabalin/oxycodone were significantly improved in the general health domain (P = .048, ANCOVA) while patients in the pregabalin/placebo obtained significant improvement in the mental-health domains (P = .004, ANCOVA) (Table 2). The highest dose/maximum tolerated dose of pregabalin at 600 mg/day was achieved in 52% (n = 14/27) of patients treated with pregabalin/oxycodone compared with 57% (n = 17/30) of patients treated with pregabalin/placebo. The average pregabalin dose for patients in the pregabalin/oxycodone group was 227.6 mg/day and 230.6 mg/day for patients in the pregabalin/placebo group. There was no significant difference (P > .05) between the pregabalin/oxycodone group and the pregabalin/ placebo group in the overall mean daily dose for concomitant rescue medication of paracetamol evaluated from the patient study diaries.
The occurrence of adverse events was comparable between the pregabalin/oxycodone group (89%) and the pregabalin/placebo group (80%) (P = .476, Fisher’s exact test), with the overall rating for most of the adverse events being mild in intensity (77–88%) regardless of the treatment group (Table 3). The most commonly reported adverse effects were dizziness, drowsiness, constipation, nausea, headache, and tiredness regardless of the treatment group (Table 3). Of these commonly seen adverse events, constipation and itch were significantly higher in the pregabalin/oxydocone group compared with the pregabalin/placebo group (P < .05, Fisher’s exact test). One patient in the pregabalin/oxycodone group had angioedema during the study but it was not considered to be associated with the study medication but rather due to a change in the patient’s antihypertensive medication. Weight gain of $4% was reported in 8.6% of patients in the pregabalin/oxycodone group and 10.7% of patients in the pregabalin/placebo group. None of the patients experienced weight gain >7% regardless of treatment group. Four patients (15%) in the pregabalin/oxycodone group discontinued the study due to adverse events and none (0%) of the patients in the pregabalin/placebo group discontinued due to adverse events. Of the 4 patients who discontinued in the pregabalin/oxydocone group, 3 withdrew during the first week of treatment with oxycodone alone due to nausea, vomiting, dizziness, and drowsiness. The 4th patient withdrew during the 4th week of treatment with oxycodone and pregabalin at 300 mg/day due to dizziness, drowsiness, and hallucination. One patient in the pregabalin/placebo group discontinued due to lack of treatment efficacy.
Discussion This study was designed to evaluate the efficacy, safety, and tolerability of a combination of a low, fixed, daily dose of oxycodone at 10 mg/day with pregabalin, relative to placebo with pregabalin, in the treatment of PHN and PDN. The primary efficacy measure demonstrated that there was no significant difference when a low dose of oxycodone 10 mg/day was added to pregabalin. Although a low dose of oxycodone at 10 mg/day has been shown to be effective in the treatment of nociceptive pain when combined with other analgesics,25,33 there was no apparent additional benefit when administered in combination with pregabalin for the treatment of neuropathic pain in the present study.
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Pregabalin and Oxycodone, Clinical Trial in PHN and PDN
Table 2.
Summary of Mean Change in Efficacy Measures from Baseline to Endpoint PREGABALIN/OXYCODONE
PREGABALIN/PLACEBO
MEAN COMPARISON
MEASURES
N
MEAN
SD
N
MEAN
SD
Pain score Sleep interference score Neuropathic pain scale Intense Sharp Hot Dull Cold Sensitive Itchy Unpleasant Deep Surface NPS 10 Short form-36 Physical function Role physical Bodily pain General health Vitality Social function Role emotional Mental health Physical summary Mental summary Profile of Mood States Tension Anxiety Depression Dejection Anger Hostility Vigor Activity Fatigue Inertia Confusion Bewilderment Total Mood Disturbances TMTB Time to complete Number of error
26 26
3.59 2.82
2.35 3.21
29 29
4.03 3.93
2.33 2.7
DIFFERENCE .44 .12
P VALUE
26
2.46 2 1.92 1.69 .57 2.15 1.65 2.03 1.34 2.15 18
3.24 3.44 3.9 2.63 2.48 3.19 2.27 3.07 3.27 3.3 23.07
29
3 2.41 2.48 2.31 0.41 1.82 .89 2.41 2.24 2.13 20.13
2.87 3.75 3.51 3.47 1.59 2.81 2.25 2.41 3.05 2.92 18.66
.54 .41 .56 .62 .16 .33 .76 .38 .9 .02 2.13
.89 .04* .005* .53 .03* .17 .78 .16 .51 .24 .25
23
6.73 18.47 13.43 7.47 7.39 12.43 12.43 6.6 4.39 3.86
17.29 51.24 18.6 19.82 22.45 27.77 47.19 18.66 8.78 11.16
28
7.14 24.1 18 2 12.32 54.75 20.82 16.35 3.1 7.82
14.74 43.29 21.16 10.09 18.07 34.85 47.28 13.46 7.05 9.06
.41 5.63 4.57 5.47 4.93 42.32 8.39 9.75 1.29 3.96
.74 .09 .29 .04* .06 .81 .38 .004* .83 .03*
24
2.62 3.12 1.58 2.87 2.16 1.04 13.37
6.49 8.17 5.57 6.32 6.23 3.54 30.49
28
3.28 2.67 3.46 3.07 3.14 .57 16.25
3.44 6.56 3.44 5.59 4.47 3.50 15.87
.66 .45 1.88 .2 .98 .47 2.88
.65 .13 .56 .21 .95 .09 .13
21
.19 .19
1.69 1.16
24
.16 .33
1.2 2.03
.03 .14
.05 .72
.07 .19
Abbreviations: N, number of patients; SD, standard deviation; NPS, neuropathic pain scale; TMTB, trail making test B. NOTE. Difference means comparison between pregabalin/oxycodone and pregabalin/placebo in the mean change from baseline (visit 2) to endpoint (visit 4) and P value was based on analysis of covariance using baseline score as a covariate. *P value is significant.
In previous studies, the effective doses of pregabalin in the treatment of neuropathic pain have been found to be between 300 and 600 mg/day17,27,28 whereas at 75 mg/day, there was no demonstrated benefit over the placebo.17 The findings from the present preliminary study suggest the possibility of a benefit of combining a low dose of oxycodone with lower doses of pregabalin in the treatment of PHN and PDN in the clinical setting. This remains to be examined in future investigations in larger clinical trials conducted over a longer period. As the present study used forced titration to the maximum tolerated dose or the maximum dose of pregabalin (600 mg/day), the proportion of patients who achieved treatment success and a pain reduction of $50% at higher doses of pregabalin in the pregabalin/placebo group may have contributed to the overall similar levels of treatment efficacy found between the 2 groups in this study.
Furthermore, the patient population in this study comprised patients with either PHN or PDN. The mean duration of PDN in the pregabalin/oxycodone group was longer at 4.5 years compared with 2.9 years for patients in the pregabalin/placebo group. This may have reduced the overall efficacy of treatment in the pregabalin/oxycodone group relative to the pregabalin/placebo group, as patients with long-term PDN may potentially have more advanced neuropathy that is less responsive to treatment with most agents.18 Moreover, a greater proportion of female patients (52%) in the pregabalin/placebo group than the pregabalin/oxycodone group (33%) may have potentially affected the efficacy of a treatment in this study, as female gender is associated with a stronger placebo effect compared with male patients.11 This may have contributed to the strong placebo effect (35%) in the pregabalin/placebo group. Despite the use of a block randomization design, the present
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469
Adverse Events with an Incidence Greater Than 5%
80
Table 3. Pgb/oxy
65.6
Pgb/pla
60
55.2 53.8
% of Patients
46.2 41.1 34.5 23.1 20
0
Oxy/pla
PGB/PLA N = 30
57.7
50.0
40
PGB/OXY N = 27
62.1
Pgb 150mg/d Pgb 600mg/d Pgb 75mg/d Pgb 300mg/d
Figure 3. Responder rates (based on $50% pain reduction from baseline to endpoint) at each different dosage level. Pgb/oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo; week 1, baseline; week 2, oxycodone/placebo; week 3, pregabalin 75 mg/day and oxycodone/placebo; week 4, pregabalin 150 mg/day and oxycodone/placebo; week 5, pregabalin 300 mg/ day and oxycodone/placebo; week 6, pregabalin 600 mg/day and oxycodone/placebo
study still resulted in an imbalance between the 2 groups in the above-mentioned patient characteristics. Given the preliminary nature of the present study and the high response rate observed in the group administered placebo in combination with pregabalin, this made it difficult to assess whether or not there was a significant effect of oxycodone relative to placebo. Thus, the results of the primary efficacy outcome of this study would best be used to design future studies to more thoroughly assess the effectiveness of this combination of analgesic agents. Future studies involving titration of patients to efficacy rather than forced titration to the maximum dose of pregabalin at 600 mg/day would have an improved ability to detect significant differences between the placebo/pregabalin and oxycodone/pregabalin treatment groups at the lower doses of pregabalin. This has been shown in the present study such that there was a nonsignificant trend for a low dose of oxycodone at 10 mg/day, combined with lower doses of pregabalin at 75 and 150 mg/day, to produce a treatment success of at least a 2-cm drop and <4 cm on the VAS, in a greater proportion of patients in the pregabalin/oxycodone group compared with patients in the pregabalin/placebo group.The secondary efficacy measures including the NPS, SF-36, and POMS were improved in both treatment groups at the end of study. These secondary efficacy measures demonstrated similar levels of efficacy between the 2 treatment groups. The occurrence of adverse events was comparable between the pregabalin/oxycodone (89%) and the pregabalin/placebo group (80%). Only constipation and itch were reported to be significantly higher in the pregabalin/oxycodone group than in the pregabalin/placebo group. These adverse events may be caused by oxycodone, as they are commonly seen with all opioid analge-
ADVERSE EVENTS
N
(%)
N
(%)
P VALUEz
Dizziness Drowsiness Constipation Nausea Headache Tiredness Itch Vomiting Sleepiness Visual disturbances Hallucination Imbalance Sweating Tremor Diarrhea Peripheral edema
22 19 18 13 6 6 5 3 3 3 2 2 2 2 1 1
82 70 67 48 22 22 19 11 11 11 7 7 7 7 4 4
17 14 8 8 6 6 0 2 0 2 0 2 0 1 3 3
57 47 27 27 20 20 0 7 0 7 0 7 0 3 10 10
.052 .107 .0035* .108 1 1 .019* .659 .1 .659 .219 1 .219 .598 .613 .613
Abbreviations: Pgb/oxy, pregabalin/oxycodone; Pgb/pla, pregabalin/placebo. *P < .05. zFisher’s exact test.
sics. Nevertheless, the present study showed that the occurrence of opioid-related adverse events was lower compared with a previous study that used higher doses of oxycodone (20–120 mg/day).10 In the previous study, constipation, somnolence, nausea, dizziness, and vomiting were shown to be significantly higher in the oxycodone group compared with the placebo group.10 Most of the adverse events that occurred in this study were well tolerated and rated as mild in intensity, regardless of the treatment group. There were no serious drug-related adverse events reported. Four patients in the pregabalin/oxycodone group withdrew from the study, 3 of whom withdrew during the first week of the study while taking oxycodone alone. This suggests that the intolerable adverse events which occurred in this study were due to oxycodone alone and that the use of a low dose of oxycodone (10 mg/day) in combination with pregabalin does not cause synergistic or additive adverse events. The strengths of the present study include the use of a randomized double-blind design to limit possible bias, use of multiple measures to assess all aspects of efficacy and safety, and an adequate dose range for the assessment of a dose-response relationship between the combination of pregabalin/oxycodone relative to pregabalin alone. Limitations of the present study include small sample size making it difficult to draw firm conclusions. However, the present study findings provide a solid basis for the design of a larger future study to further assess the efficacy of a combination of oxycodone and pregabalin in the treatment of PHN and PDN. The present 6-week study was designed to mimic the treatment paradigm used in clinical practice and not intended to determine whether the analgesic effects produced by a combination
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Pregabalin and Oxycodone, Clinical Trial in PHN and PDN
of oxycodone and pregabalin are long lasting. Another limitation of the present study includes the use of pregabalin in an open-label forced-titration dosing regimen such that patients and investigators were aware of the increasing dose of pregabalin. This may have contributed to the magnitude of the placebo effect observed in this study such that greater pain relief with higher pregaba-
lin dosages resulted from knowledge of dosage escalation and not to the pharmacologic effects of the dosage increases. In summary, this preliminary study has shown that coadministration of a low-dose oxycodone at 10 mg/day with pregabalin did not enhance pregabalin efficacy in patients with PHN or PDN.
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